In recent years, the incidence of multiple primary lung cancer (MPLC) has been increasing, and it cannot be ignored in clinical practice. The treatment of MPLC is still controversial, but surgical treatment is recognized as the most important treatment. However, current studies have shown that the treatment of MPLC needs to develop multimodal treatment according to different patients. This review summarizes multiple treatment method for MPLC, including surgery, ablation, chemotherapy, radiotherapy, targeted therapy, and immunotherapy in order to enhance understanding of MPLC treatment.
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Humans ; Lung Neoplasms/surgery* ; Immunotherapy ; Combined Modality Therapy

Objective To investigate the effects of different culture conditions(RPMI-1640,DMEM and DMEM/F12 medium)on the passage of MPM cells isolated from the tissues of Malignant pleural mesothelioma(MPM),and to study the effects of CDKN2B on the proliferation,invasion and apoptosis of MPM cells.Methods MPM cells were isolated from MPM tissues and cultured in RPMI-1640,DMEM and DMEM/F12 medium,respectively.Cell proliferation was examined by CCK-8,and the nuclei and chromosomes were observed by Wright-Giemsa staining.Fluorescence intensities of Calretinin,CD141,CK5,EMA and WT-1 were conducted by immunofluorescence assay.The mRNA and protein expression of CDKN2B were detected by RT-qPCR and Western blot,respectively.Transwell was used to detect cell invasion and flow cytometry was used to detect cell apoptosis.Results The established MPM cells showed good viability when passaged to the 10th generation in RPMI-1640,DMEM and DMEM/F12 cultures,and the MPM markers Calretinin,CD141,CK5,EMA and WT-1 were all expressed in the cells.The viability of MPM cells in RPMI-1640 culture medium was relatively stable.CDKN2B was downregulated in MPM cells(P<0.05),and overexpression of CDKN2B significantly suppressed the proliferation(P<0.05),invasion(P<0.05)and epithelial interstitial transformation of MPM cells(P<0.01),and promoted the apoptosis(P<0.01).Conclusion The established MPM cells were stably passaged in RPMI-1640 culture medium,and CDKN2B may be a potential target for the diagnosis and treatment of MPM.

Objective:To compare the safety of the generic and the original regorafenib tablets.Methods:Two single center, randomized, open-label, 2-period self-crossover phase I clinical trials (single dose) were conducted under fasting condition and with low-fat meal respectively in healthy adult volunteers. The test preparation (T) of regorafenib was produced by Beijing Sl Pharmaceutical Co.,Ltd. and the reference preparation (R) was produced by Bayer HealthCare Pharmaceuticals Inc. In the 2 trials, male healthy subjects were randomly divided into 2 groups, respectively, and took 2 times of the preparations with different order in each group, which were R-T group (subjects took R on day 1 and then T on day 13) and T-R group (subjects took T on day 1 and then R on day 13). The subjects took drugs under fasting condition and with low-fat meal in the 2 trials respectively. After medication, vital signs detection, electrocardiogram, general physical examination, blood routine, blood biochemical, coagulation function, and other tests were performed regularly, and the occurrence of adverse events (AEs) were recorded and the severity of AEs was assessed.Results:Sixty-four subjects were enrolled in the trial under fasting condition, including 32 in the T-R group and 32 in the R-T group, and the safety data was obtained from 61 and 57 subjects taking T and R, respectively. Seventy-six subjects were included in the postprandial trial, including 38 in the T-R group and 38 in the R-T group, and the safety data was obtained from 74 subjects taking T and R, respectively. In the 2 trials, there was no significant difference in the incidence of AEs between subjects taking T and those taking R [41.0% (25/61) vs. 31.6% (18/57), χ2=1.125, P=0.289; 56.8% (42/74) vs. 45.9% (34/74), χ2=0.183, P=0.188]. A total of 230 AEs occurred in the 2 trials, of which 228 cases were grade 1 (99.1%, 131 and 97 AEs occurred in subjects taking T and R, respectively), 2 cases were grade 2 (0.9%, 1 AE occurred in subjects taking T and R, respectively), and no grade ≥ 3 AEs occurred. The types of AEs occurred in the 2 trials were the same, of which bradycardia was the most common, followed by prolonged QT interval of ECG. All ECG abnormalities were found during routine examinations, and no subjects had obvious clinical symptoms. Conclusion:The safety of the generic and the original regorafenib tablets was consistent after a single dose administration under fasting condition and with low-fat meal.

Objective:To compare the safety of the generic and the original regorafenib tablets.Methods:Two single center, randomized, open-label, 2-period self-crossover phase I clinical trials (single dose) were conducted under fasting condition and with low-fat meal respectively in healthy adult volunteers. The test preparation (T) of regorafenib was produced by Beijing Sl Pharmaceutical Co.,Ltd. and the reference preparation (R) was produced by Bayer HealthCare Pharmaceuticals Inc. In the 2 trials, male healthy subjects were randomly divided into 2 groups, respectively, and took 2 times of the preparations with different order in each group, which were R-T group (subjects took R on day 1 and then T on day 13) and T-R group (subjects took T on day 1 and then R on day 13). The subjects took drugs under fasting condition and with low-fat meal in the 2 trials respectively. After medication, vital signs detection, electrocardiogram, general physical examination, blood routine, blood biochemical, coagulation function, and other tests were performed regularly, and the occurrence of adverse events (AEs) were recorded and the severity of AEs was assessed.Results:Sixty-four subjects were enrolled in the trial under fasting condition, including 32 in the T-R group and 32 in the R-T group, and the safety data was obtained from 61 and 57 subjects taking T and R, respectively. Seventy-six subjects were included in the postprandial trial, including 38 in the T-R group and 38 in the R-T group, and the safety data was obtained from 74 subjects taking T and R, respectively. In the 2 trials, there was no significant difference in the incidence of AEs between subjects taking T and those taking R [41.0% (25/61) vs. 31.6% (18/57), χ2=1.125, P=0.289; 56.8% (42/74) vs. 45.9% (34/74), χ2=0.183, P=0.188]. A total of 230 AEs occurred in the 2 trials, of which 228 cases were grade 1 (99.1%, 131 and 97 AEs occurred in subjects taking T and R, respectively), 2 cases were grade 2 (0.9%, 1 AE occurred in subjects taking T and R, respectively), and no grade ≥ 3 AEs occurred. The types of AEs occurred in the 2 trials were the same, of which bradycardia was the most common, followed by prolonged QT interval of ECG. All ECG abnormalities were found during routine examinations, and no subjects had obvious clinical symptoms. Conclusion:The safety of the generic and the original regorafenib tablets was consistent after a single dose administration under fasting condition and with low-fat meal.

Objective:To evaluate the role of spinal mammlian target of rapamycin (mTOR)/ribosomal S6 kinase 1 (S6K1)/glioma associated oncogene homolog 1 (Gli1) signaling pathway in chronic morphine tolerance in mice.Methods:Healthy male Kunming mice, aged 8-10 weeks, weighing 23-25 g, were used in the study.The experiment was performed in two parts.Experiment I Fifty mice were randomly assigned into 2 groups: normal saline group (group S, n=10) and morphine group (group M, n=40). In M and S groups, morphine and normal saline 10 mg/kg were injected subcutaneously, respectively, twice a day for 7 consecutive days.The thermal pain threshold (TPT) was measured and the maximum analgesic effect percentage (MPE) was calculated at 1 day before administration and 30 min after the last administration every day.Ten mice in each group were randomly selected and sacrificed after measurement of TPT at 1, 3, 5 and 7 days after administration in group M and after the last measurement of TPT in group S, and the lumbar segment (L 4-6) of the spinal cord was removed.Experiment Ⅱ Forty mice were randomly divided into 4 groups ( n=10 each): KU-0063794+ morphine group (group KU+ M), dimethyl sulfoxide (DMSO)+ morphine group (group DM+ M), morphine+ KU-0063794 group (group M+ KU) and morphine + DMSO group (group M+ DM). Morphine 10 mg/kg was injected subcutaneously twice a day for 7 consecutive days in 4 groups.At 1-3 days of morphine injection, mTOR specific inhibitor KU-0063794 200μl (1 μg/μl) and 10% DMSO 200 μl was injected intraperitoneally in KU+ M group and DM+ M group at 30 min before administration twice a day.At 5-7 days of morphine injection, KU-0063794 200μl (1 μg/μl) or 10% DMSO 200 μl was injected intraperitoneally in group M+ KU or group M+ DM at 30min before administration, respectively, twice a day.TPT was measured and MPE was calculated at 1 day before morphine injection and at 30 min after the last administration every day.The animals were sacrificed after the last measurement of TPT, and the lumbar segment (L 4-6) of the spinal cord was removed for determination of the expression of spinal mTOR, phosphorylated mTOR (p-mTOR), S6K1, phosphorylated S6K1 (p-S6K1) and Gli1 (using Western blot). Results:Experiment Ⅰ Compared with group S, MPE was significantly increased at each time point after administration at 3, 5 and 7 days after administration, expression of spinal p-mTOR, p-S6K1 and Gli1 was significantly down-regulated ( P<0.05), and no significant change was found in mTOR and S6K1 in group M ( P>0.05). Experiment Ⅱ Compared with group DM+ M, MPE was significantly decreased at 3-7 days after morphine injection, expression of p-mTOR, p-S6K1 and Gli1 in spinal cord was down-regulated ( P<0.05), and no significant change was found in expression of mTOR and S6K1 in group KU+ M ( P>0.05). Compared with group M+ DM, MPE was significantly increased at 6-7 days after morphine injection, expression of p-mTOR, p-S6K1 and Gli1 in spinal cord was down-regulated ( P<0.05), and no significant change was found in mTOR and S6K1 in group M+ KU ( P>0.05). Conclution:Spinal mTOR/S6K1/Gli1 signaling pathway is involved in the development and maintenance of chronic morphine tolerance in mice.